Prognostic Value of CpG Island Hypermethylation at PTGS2 , RAR-beta , EDNRB , and Other Gene Loci in Patients Undergoing Radical Prostatectomy

• Published in: European urology 2007-03, Vol.51 (3), p.665-674
• Main Authors: Bastian, Patrick J, Ellinger, Jörg, Heukamp, Lukas C, Kahl, Philip, Müller, Stefan C, von Rücker, Alexander
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; CpG Islands; DNA Methylation; Humans; Male; Middle Aged; Prognosis; Prostatectomy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - surgery; Urology
• ISSN: 0302-2838
• DOI: 10.1016/j.eururo.2006.08.008

Abstract Objectives To evaluate CpG island hypermethylation in a set of candidate genes in prostate cancer (pCA) and its relationship to clinicopathologic parameters and a nomogram predicting prostate-specific antigen (PSA) recurrence after radical prostatectomy. Materials and methods Tissues of 78 prostate carcinomas, 32 benign prostate hyperplasias (BPHs), and prostate cell lines (LNCaP, DU145, PC3, BPH-1) were examined with MethyLight polymerase chain reaction at 13 gene loci ( APC, CDC6, CTNNB1, E-Cadherin, EDNRB, FGFR2, GSTP1, NAB2, PKCmu, PTGS2, RAR-beta, RASL11A, WWOX ). Results APC, RAR-beta, PTGS2, GSTP1, EDNRB , and CTNNB1 (83%, 71%, 65%, 33%, 14%, 9%, respectively) were methylated in pCA but rarely or not methylated in BPH. NAB2 and CDC6 were hypermethylated frequently in pCA (92%, 67%, respectively) and in BPH (91%, 59%, respectively). FGFR2, WWOX, E-Cadherin, PKCmu , and RASLL1A did not display noteworthy methylation in pCA (0–1%) or in BPH. CpG island hypermethylation at APC , retinoic acid receptor beta ( RAR-beta ), and PTGS2 discriminated with a sensitivity of 65–83% and a specificity of 97–100% between BPH and pCA. The combination of various genes increased the diagnostic expressiveness. PTGS2 hypermethylation correlated with seminal vesicle infiltration ( p = 0.047), capsular penetration ( p = 0.004), and pT stage ( p = 0.014). RAR-beta methylation was accompanied by a higher cumulative Gleason score ( p = 0.042). The probability of PSA-free-survival calculated with a Kattan nomogram correlated inversely with CpG island hypermethylation at EDNRB, RAR-beta , and PTGS2 . All prostate cancer cell lines displayed a varying degree of demethylation after 5-aza-2′deoxycytidine treatment. Conclusions CpG island hypermethylation at various gene loci is frequent in prostate cancer and can distinguish between neoplastic and noncancerous tissue. Furthermore, hypermethylation at PTGS2, RAR-beta , and EDNRB inversely correlated with PSA-free-survival according to a Kattan nomogram and has potential prognostic value.